Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

  • Sci Adv. 2023 May 3;9(18):eadf0115. doi: 10.1126/sciadv.adf0115.
Luke T Izzo  1  2 ,  Sophie Trefely  1  2  3 ,  Christina Demetriadou  1  2  3 ,  Jack M Drummond  1  2 ,  Takuya Mizukami  4 ,  Nina Kuprasertkul  1  2  5 ,  Aimee T Farria  1  2 ,  Phuong T T Nguyen  1  2 ,  Nivitha Murali  1  2 ,  Lauren Reich  1  2 ,  Daniel S Kantner  3 ,  Joshua Shaffer  1  2 ,  Hayley Affronti  1  2 ,  Alessandro Carrer  1  2 ,  Andrew Andrews  4  6 ,  Brian C Capell  5 ,  Nathaniel W Snyder  3 ,  Kathryn E Wellen  1  2
Affiliations
  • 1. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3. Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 4. Department of Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 5. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6. Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403, USA.
PMID: 37134161 DOI: 10.1126/sciadv.adf0115
Abstract

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether Other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated Cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.

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